U.S. Pat. No.4,752,619 discloses and claims a method and composition for the nutritional treatment of chronic renal failure. This reference discloses a mixture of salts which are the reaction product of a basic L-amino acid selected from the group consisting of L-ornithine, L-lysine and L-histidine and a branched-chain .alpha.-keto analog of an essential amino acid selected from the group consisting of .alpha.-ketoisocaproate, .alpha.-ketoisovalerate, and .alpha.-keto-.beta.-methylvalerate. The '619 reference claims compositions of no more than five of said salts in recited proportions. The specification and all of the examples recited in the '619 reference relate to mixtures of five salts. The '619 reference does not disclose nor does it contemplate the use of a four salt formulation which provides unexpected product stability while maintaining the equivalent nutritional values. This reference also fails to disclose or anticipate the benefits of the instant four salt composition. These benefits include, but are not limited to lower ingredient costs, increased product stability, reduced quality control, improved odor, improved flavor and improved product homogeneity.
European patent application No. 295,166 discloses pharmaceutical compositions for the treatment of uremia which comprises keto-acid salts of ornithine, histidine and lysine. This reference fails to disclose or anticipate that a specific nutritional formulation of four keto salts would evidence enhanced thermal stability and palatability while at the same time supplying the necessary nutritional requirements to the uremic patient.
U.S. Pat. No. 4,677,121 discloses and claims a method of reducing muscle protein degradation in patients suffering from such degradation comprising administering to said patient an effective amount of a composition consisting essentially of .alpha.-ketoisocaproic acid (ketoleucine) or a pharmaceutically acceptable salt thereof. U.S. Pat. No.4,352,814 discloses and claims a composition useful for providing essential and semi-essential amino acids to the body for the treatment of renal disease in humans. The composition comprises the reaction product of the following compounds: .alpha.-ketoisovaleric acid, .alpha.-ketoisocaproic acid, .alpha.-keto-.beta.-methylvaleric acid, histidine, threonine, and lysine. Said reaction product being formed in aqueous medium followed by removal of water. These references fail to suggest or disclose the unexpected benefits that can be realized with the specific four salt formulation of the instant invention.
U.S. Pat. No. 4,320,146 is directed to novel compounds prepared by reacting ornithine or arginine with .alpha.-keto analogs of branched chain essential amino acids namely valine, leucine and isoleucine. This reference discloses that the compounds are useful either individually or as a mixture in the treatment of hepatic disorders. The reference also suggests that the compounds of the reference have utility in the treatment of renal failure. More specifically, this reference is directed to a composition for promoting protein synthesis which comprises a carrier and an effective amount of at least one compound having the formula AK.x H.sub.2 O wherein A is selected from the group consisting of arginine and ornithine; K is an .alpha.-keto analog of a branched-chain essential amino acid and x varies from 0 to about 1. This reference fails to disclose or suggest the specific formulation of the instant invention which unexpectedly possesses enhanced thermal stability and palatability.
U.S. Pat. No. 4,296,127 discloses a compound useful in the treatment of nitrogen wasting disorders and protein malnutrition which comprises a compound of the formula AN.x H.sub.2 O wherein A is selected from the group consisting of essential amino acids and semi-essential amino acids, N is selected from the group consisting of .alpha.-keto and .alpha.-hydroxy analogs of essential or semi-essential amino acids, but when A is L-ornithine or L-arginine, N is not an .alpha.-keto analog of a branched chain essential amino acid, and x may be zero or a positive number which need not be an integer.
U.S. Pat. No. 4,228,099 discloses and claims compounds which are prepared by reacting ornithine or arginine with .alpha.-keto analogs of branched chain essential amino acids. The compounds disclosed in the '099 reference are useful either individually or as a mixture in the treatment of hepatic disorders and may also be useful in the treatment of renal failure.
Japanese Patent Journal No. Showa 54(1979)-117020 discloses an improved fluid useful in purifying body fluids. This reference discloses that the nitrogen balance in the body can be improved by adding a specified substance to the body fluid during its purification. The reference discloses that adding at least one type of .alpha.-keto-acid of an essential amino acid to the solution being used as a dialytic is beneficial.
U.S. Pat. No. 4,100,161 discloses and claims compositions containing keto-analogs of certain amino acids which are essential for humans and can be therapeutically employed in the treatment of patients restricted to low protein diets. The composition of the '161 reference consists of effective quantities of keto-acid analogs of the branched-chain essential amino acids valine, leucine and isoleucine. In similar fashion U.S. Pat. No. 4,100,160 discloses a composition capable of promoting protein synthesis and conserving nitrogen in a patient in need thereof. The composition of the '160 patent being in the form of a mixture adapted for oral or parenteral administration to subjects on a protein-restricted diet. The '160 composition comprising a mixture of effective quantities of hydroxy-acid or keto-acid analogs of the essential amino acids valine, phenylalanine, isoleucine, leucine and methionine. The '160 patent requires that at least one f the analogs of the essential amino acids be a hydroxy acid analog. Said hydroxy acid or keto-acid analog being present in the form of the acid analogs per se or salts of the acid analogs.
U.S. Pat. No. 4,100,293 discloses that certain compositions comprising keto-analogs of certain essential amino acids are useful in the treatment of hepatic disorders. In the preferred embodiment of this reference the composition is comprised of the keto-analogs of valine, phenylalanine, methionine, leucine, and isoleucine.
The prior art does not suggest or disclose the specific formulation of the instant invention which provides required nutritional values to the patient consuming a low protein diet while unexpectedly increasing product stability, providing improved odor and flavor while at the same time reducing the manufacturing costs and quality control costs.
Organic sats of basic L-amino acids and .alpha.-keto-analogs of branched chain essential amino acids are known to be useful in the treatment of hepatic disorders and for treatment of renal failure. Branched chain keto-acids and .alpha.-ketoisocaproate in particular are known to exhibit a protein sparing effect in patients with chronic renal failure. That is, branched chain keto-acids reduce urinary nitrogen loss. These keto-acids have been used to improve the nitrogen balance in patients suffering from a number of different nitrogen wasting conditions.
Keto acid analogs are also known to be adequate nutritional substitutes for several of the essential amino acids. Substitution of keto-analogs for essential amino acids makes possible a reduction in the nitrogen intake of uremic patients. The nitrogen sparing effect of keto-analogs has been clinically confirmed.
The medical community has long searched for an effective nutritional regimen for the treatment of chronic renal failure (pre-dialysis phase) which would maintain proper protein nutrition as well as energy balance while minimizing intake of protein containing foods which contribute to uremic toxicity. Protein restriction is believed to retard the rate of progression of chronic renal insufficiency.
Some of the prior art discussed above has attempted to optimize the nutritional treatment of chronic renal failure through a diet supplemented with calcium salts of essential amino acid keto-analogs. This approach, however, suffers from the fact that calcium salts of keto-analogs are known to be highly unpalatable and thus must be highly taken as coated granules or tablets. The medical community has also determined that the circulating concentrations of amino acids in the blood remain abnormal while on this particular regimen as they also do on supplements based on essential amino acids themselves.
A more recent approach replaces the calcium salts of keto-analogs with salts formed between branched chain .alpha.-keto-acids and basic L-amino acids. These salts have been found to be more soluble and less unpalatable than the calcium salts of the keto-acids and therefore, may be taken as a powder dissolved in water or fruit juice. It has been determined however, that long term storage of the prior art composition results in degradation of the composition. A viable product useful on a commercial scale must have prolonged stability while at the same time maintaining nutritional equivalence and hopefully improved palatability.
These prior art supplements are prepared by mixing up to 10 different constituents. The large number of constituents increases the difficulty of preparation of the supplement as well as the associated cost. Since shelf life of the mixture is limited by the storage stability of the least stable of the individual components of the mixture, mixtures of a large number of components tend to have a shorter shelf life than those with a relatively small number of constituents. Thus, it is desirable to obtain a supplement having fewer constituents and which demonstrates the same effectiveness in arresting the progression of chronic renal failure while maintaining proper nutrition.